The present invention is directed to a method and apparatus for treating pigmented tissues by selective photoactivation of pigments in such tissues using optical energy and more specifically two-photon excitation. This selective photoactivation may be used to effect photobleaching of such pigments or to effect photochemical conversion of such pigments into phototoxic products. Photobleaching reduces or eliminates undesirable pigmentation, for example that caused by pigments present in moles, freckles, hair follicles and tattoos. Photochemical conversion produces phototoxic products that destroy pigmented tissues, such as those pigmented tissues in pigmented tumors. The present invention is also directed to selective thermal destruction of pigmented tissues using related optical means.
Photobleaching is the transient or permanent reduction of pigmentation in pigmented tissues upon optical illumination, typically occurring during intense illumination with visible or ultraviolet light. Photobleaching occurs when photoactive pigments are photochemically transformed from a highly colored state to a less highly colored state (de-pigmentation). For example, photobleaching may be used to reduce or eliminate undesirable pigmentation present in moles and hair follicles or to destroy dyes present in tattoos. It is desired that treated tissues will exhibit localized de-pigmentation without side effects, such as irritation or cell necrosis. However, previous methods for photobleaching tissues using visible or ultraviolet light have produced undesirable collateral effects, including irritation of surrounding tissues and possible scarring at the treatment site.
In contrast to photobleaching, photochemical conversion of pigments into phototoxic products involves stimulation of localized cell necrosis in treated tissues. This is also effected by optical illumination, typically occurring when intense visible or ultraviolet light is used to illuminated susceptible pigmented tissues. Such localized necrosis may be useful for selective destruction of diseased tissues, such as those present in tumors or benign skin lesions.
More specifically, an important subset of pigmented tissues are pigmented tumors, such as melanomas, which are life threatening and highly difficult to treat. While melanomas can be treated if detected early using standard surgical, radiation or chemotherapeutic methods, these methods still do not have acceptable levels of effectiveness and produce high levels of collateral damage to normal tissue. Hence, even if detected relatively early, the prognosis is usually poor.
Further, if a melanoma has metastasized beyond the primary tumor site, less than 20% of patients will survive beyond five years. For such melanomas, there are no effective therapies. Patients diagnosed with such a metastatic melanoma will survive on average only 3–6 months after the diagnosis even with therapeutic intervention.
Further exacerbating the difficulties in treating melanomas is the fact that the incidence of melanoma in Caucasians is increasing at a rate of 6% per year. This is currently the second fastest rate of increase in cancer occurrences—second only to tobacco related cancers of the lung in women. Currently, the lifetime risk of melanoma in the U.S. is 1 in 75. Accordingly, new effective therapeutic modalities are required to treat both primary and metastatic pigmented tumors such as melanomas.
One possible approach for treating pigmented tissues involves the use of melanins, their precursors, and other endogenous or exogenous pigments.
More specifically, there are several pigments in humans that are collectively known as melanins. The function of melanins are to protect tissues from the deleterious effects of electromagnetic radiation (e.g. light). However, melanins and their precursors can also be converted to phototoxic products. For example, a melanin precursor (5-SCD) has been shown to photobind to DNA after exposure to 300 nm (ultraviolet light) illumination. Further, 5-SCD has been shown to be chemically unstable in the presence of ultraviolet (UV) illumination and oxygen, thereby suggesting that phototoxic products of the (1) Type I variety (phototoxic) or the (2) Type II variety (photocatalytic) may be produced.
Additionally, many melanoma cells are amelanotic. These cells produce melanin precursors but only small quantities of melanin. Phototoxic damage (induction of single strand breaks) to DNA by at least two precursors to melanin (5-SCD and DIHCA) has been demonstrated upon exposure to UV light. Amelanotic cells will be killed by photodynamic therapy (PDT) performed on such precursors to melanin (e.g., 5-SCD, DIHEA). Thus, melanomas can be killed by delivering energy via light.
However, utilization of such phototoxic reactions by illumination of melanin, melanin precursors, or other endogenous pigments has not previously been possible. The UV/Near UV light required for photoactivation is unable to penetrate into normal or cancerous skin (i.e. beyond 2–3 mm.) More specifically, the poor penetration of such light has produced little effect on patients whose skin tumors are larger than or at a depth greater than 3 mm. As a result, only 40–50% of patients whose tumors exceed 3 mm will survive. Accordingly, the survival rate of melanoma patients with tumors whose depth is less than 1 mm is drastically better than those who have tumors which are either located at a depth of greater than 3 mm or extend to a depth greater than 3 mm.
Previous photodynamic methods using UV/Near UV light also produced undesirable collateral effects that not only prohibited the photoconversion of melanin and prevented it from killing pigmented tissues but also was potentially dangerous to the patient. For example, UV light can create thymidine dimers which damage genetic material. DNA damage is a major and possibly the sole cause of skin cancers like melanomas. Melanin's absorbance of UV light is designed to prevent this from happening. However, UV light, chemotherapy, and ionizing radiation have recently been shown to increase the virulence of tumor cells. As a result, tumor cells when treated with UV light will have a greater mutation and error rate because the UV light can inactivate mechanisms designed to identify and correct genetic errors (in addition to creating new errors). Therefore, prior techniques were not only unable to effectively kill pigmented tissues by accessing endogenous pigments but also created side effects that could be lethal.
In many instances, the effectiveness of various photodynamic processes have been found to be markedly increased by simultaneous photoactivation and localized heating (hyperthermia). Typically, by heating the treatment zone 2–10° C. above normal temperatures, the effectiveness of PDT is increased many fold. Such heating alone, however, has not been shown to produce a significant therapeutic effect. In contrast, the inventors of the present invention have conceived that more acute localized heating (i.e., >2–10° C. temperature rise) of tissues and tissue components within the treatment zone may produce a therapeutic effect by causing thermal overload in the treated tissues.
Therefore, it is an object of the present invention to provide a method for accessing endogenous pigments in pigmented tissues so as to be able to selectively photobleach said pigments.
It is another object of the present invention to provide a method for accessing endogenous pigments in pigmented tissues so as to be able to photochemically convert said pigments into phototoxic products.
It is another object of the present invention to provide a method that will access said endogenous pigments in pigmented tissues without accessing endogenous pigments in healthy tissues surrounding said pigmented tissues.
It is another object of the present invention to provide a method that will augment the effectiveness of said photochemical conversion of said endogenous pigments in said pigmented tissues through the localized application of hyperthermia in said pigmented tissues.
It is another object of the present invention to provide a method that will photothermally destroy pigmented tissues without harming healthy tissues surrounding said pigmented tissues.